DOCSLIB.ORG

The Role of the Enterohepatic Circulation of Bile Salts and Nuclear Hormone Receptors in the Regulation of Cholesterol Homeostasis: Bile Salts As Ligands for Nuclear Hormone Receptors

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Role of the Enterohepatic Circulation of Bile Salts and Nuclear Hormone Receptors in the Regulation of Cholesterol Homeostasis: Bile Salts As Ligands for Nuclear Hormone Receptors Redinger.qxd 3/28/03 11:21 AM Page 265 ORIGINAL ARTICLE The role of the enterohepatic circulation of bile salts and nuclear hormone receptors in the regulation of cholesterol homeostasis: Bile salts as ligands for nuclear hormone receptors Richard N Redinger MD RN Redinger. The role of the enterohepatic circulation of bile Le rôle de la circulation entérohépatique des salts and nuclear hormone receptors in the regulation of sels biliaires et des récepteurs de l’hormone cholesterol homeostasis: Bile salts as ligands for nuclear hormone receptors. Can J Gastroenterol 2003;17(4):265-271. nucléaire dans la régulation de l’homéostasie cholestérolique : Les sels biliaires comme The coordinated effect of lipid activated nuclear hormone receptors; ligands des récepteurs de l’hormone nucléaire liver X receptor (LXR), bound by oxysterol ligands and farnesoid X receptor (FXR), bound by bile acid ligands, act as genetic transcrip- L’effet coordonné des récepteurs nucléaires de l’hormone activée par les tion factors to cause feed-forward cholesterol catabolism to bile acids lipides, du récepteur X hépatique (RXH), lié par les ligands d’oxystérol et and feedback repression of bile acid synthesis, respectively. It is the le récepteur X famésoïde (RXF), liés par les ligands acidobiliaires, agit coordinated action of LXR and FXR, each dimerized to retinoid X comme des facteurs de transcription génétique afin de provoquer, respec- receptor, that signal nuclear DNA response elements to encode pro- tivement, un catabolisme cholestérolique non récurrent des sels biliaires et teins that prevent excessive cholesterol accumulation and bile salt une répression à rétroaction de la synthèse de l’acide biliaire. C’est l’action toxicity, respectively. LXR helps prevent hypercholesterolemia by coordonnée du RXH et du RXF, chacun étant dimérisé au récepteur X enhancing transporters for cholesterol efflux that enhance reverse rétinoïde, qui signale aux éléments de réponse de l’ADN nucléaire d’en- cholesterol transport, while FXR enhances intestinal reabsorption coder les protéines qui, respectivement, empêchent l’accumulation and preservation of bile salts by increasing the ileal bile acid binding cholestérolique excessive et la toxicité des sels biliaires. Le RXH con- protein. FXR also targets sodium taurocholate cotransport peptide tribue à prévenir l’hypercholestérolémie en accentuant l’efflux and bile salt export pump (protein) genes to limit bile salt uptake and cholestérolique des transporteurs, qui accroît le transport cholestérolique enhance export, respectively, which prevents bile salt toxicity. Other inversé, tandis que le RXF favorise la réabsorption intestinale et la préser- nuclear hormone receptors such as pregnan X receptor, which share vation des sels biliaires en augmentant la liaison de la protéine à l’acide biliaire iléal. Le RXF cible également le peptide de cotransport du tauro- the obligate partner, retinoid X receptor, and vitamin D receptor also cholate sodique et les gènes de la pompe (à protéines) d’exportation des function as bile acid sensors to signal detoxification by hydroxylation sels biliaires, respectivement, lesquels empêchent la toxicité des sels bi- of toxic bile acids. Pharmacologically targeted receptor agonists (or liaires. D’autres récepteurs nucléaires de l’hormone, tels que le récepteur antagonists) may be developed that alter cholesterol and bile salt X pregnan, qui partage le partenaire strict, le récepteur X rétinoïde, et le concentrations by modulating nuclear hormone receptors and/or récepteur de la vitamine D, fonctionnent également comme des senseurs their coactivators or corepressors to positively affect cholesterol de l’acide biliaire afin de signaler la détoxification par l’hydroxylation des homeostasis and bile salt metabolism. It is the coordinated transcrip- acides biliaires toxiques. Des agonistes (ou antagonistes) récepteurs ciblés tion factor action of LXR, which responds to ligand binding of circu- par la pharmacologie peuvent être mis au point pour altérer les concen- lating oxysterols in both liver and peripheral tissues, and FXR trations de cholestérol et de sels biliaires en modulant les récepteurs de responding to bile salts within the enterohepatic circulation that l’hormone nucléaire, leurs coactivateurs ou leurs corépresseurs à avoir un make possible the regulation of cholesterol and bile acid homeostasis. effet positif sur l’homéostasie cholestérolique et le métabolisme des sels biliaires. C’est l’action coordonnée des facteurs de transcription du RXH Key Words: Bile acid; Cholesterol homeostasis; Nuclear hormone qui réagit à la liaison ligand des oxystérols circulants tant dans le foie que receptors dans les tissus périphériques, et du RXF qui réagit aux sels biliaires dans la circulation entérohépatique qui rend possible la régulation du cholestérol et l’homéostasie de l’acide biliaire. t is well known that bile salts (note: bile acids become bile as other lipids such as monoglycerides, fatty acids and fat- Isalts at physiological cellular pH=7. In the present review, soluble vitamins for luminal digestion and consequent intes- the term bile acid is used to denote their state at the time of tinal absorption (1). The physiochemical mechanisms under- synthesis while the designation bile salt is used to reflect their lying these actions were worked out by seminal studies on chemical state in body solutions as sodium and potassium salts biliary lipids and intraluminal intestinal digestion, thus provid- of bile acids) have major biological effects related to their abil- ing a better understanding of the pathogenesis of gallstone dis- ity to solubilize cholesterol in bile and in the intestine, as well ease (2) and luminal gut lipid malabsorption (3). However, the Department of Medicine, University of Louisville, Louisville, Kentucky, USA Correspondence and reprints: Dr Richard Redinger, Department of Medicine, University of Louisville, 530 South Jackson Street, Third floor, Louisville, Kentucky 40292 USA. Telephone 502-852-5241, fax 502-852-6233, e-mail [email protected] Received for publication June 10, 2002. Accepted December 19, 2002 Can J Gastroenterol Vol 17 No 4 April 2003 ©2003 Pulsus Group Inc. All rights reserved 265 Redinger.qxd 3/28/03 11:21 AM Page 266 Redinger role of nuclear hormone receptors within the enterohepatic ostasis. Bile acids, the catabolic end product of cholesterol, are circulation of bile salts has not been fully appreciated, which much more hydrophilic than cholesterol and in fact act as relates to the molecular regulation of bile salt and cholesterol detergents by forming mixed micelles with cholesterol and oth- homeostasis that prevents intrahepatic bile salt toxicity and er lipids for their transport to and absorption from the intestine abnormal accumulation of cholesterol or their esters, respec- (2). Bile salts themselves can become toxic at high levels in tively. Recently, through major advances in research relating cells, so that their intracellular levels must also be regulated in to molecular signaling by ligand binding to nuclear hormone addition to that of cholesterol (15). receptors, it is now apparent that bile salts themselves act as Insight into the physiological complexity contributing to ligands to nuclear receptors and thereby play an increasingly the regulation of bile salt metabolism first became apparent important role in preserving cholesterol homeostasis in mam- with the description of an enterohepatic circulation of bile mals, including man (4-8). The present review is intended to salts, which anatomically defined the movement of bile salts help the clinical gastroenterologist/hepatologist understand by following their synthesis as bile acids in the liver; secretion the role of the molecular regulation of bile salts and cholesterol as bile salts into the intestine by the biliary tract; their avid homeostasis both within and complementary to the entero- reabsorption in the distal ileum; and consequent transport hepatic circulation of bile salts. Due to the limited scope of the back to the liver in portal blood (16). More than 95% of bile present review and space limitations, additional reviews are salt secretion is thereby preserved with the body, so that less listed in the bibliography for details of molecular structure and than 5% of the bile salt pool is lost by fecal elimination. other nuclear hormone receptors that control other aspects of Excessive bile salt loss also must be avoided, because bile salts lipid metabolism (9-11). have colonic effects on cyclic adenosine monophosphate- induced water secretion and will produce secretory diarrhea if EVOLUTIONARY IMPERATIVES FOR lost excessively into the colon (ie, bile salt enteropathy) (17). CHOLESTEROL METABOLISM This fine-tuned circulation of the bile salt pool of two to four The need for bile salts in human evolution traces back to the grams, which cycles several times a meal and a total of 10 or need for cells to synthesize cholesterol as well as to control its more times daily, produces a total effective feed-forward secre- excessive accumulation by metabolic degradation. As life pro- tion of 30 grams of bile salt per day. Thus, an economy of the gressed from non-nucleated prokaryotes to eurokaryotes, with enterohepatic circulation of bile salts is necessary for preserva- the development of multiorganelle structures involving com- tion of the bile salt pool (18). For this economy to be realized for the maintenance of a constant bile salt pool, feedback con- plex membrane
Load more

Recommended publications
  • Impaired Hepatic Drug and Steroid Metabolism in Congenital Adrenal
    European Journal of Endocrinology (2010) 163 919–924 ISSN 0804-4643 CLINICAL STUDY Impaired hepatic drug and steroid metabolism in congenital adrenal hyperplasia due to P450 oxidoreductase deficiency Dorota Tomalik-Scharte1, Dominique Maiter2, Julia Kirchheiner3, Hannah E Ivison, Uwe Fuhr1 and Wiebke Arlt School of Clinical and Experimental Medicine, Centre for Endocrinology, Diabetes and Metabolism (CEDAM), University of Birmingham, Birmingham B15 2TT, UK, 1Department of Pharmacology, University Hospital, University of Cologne, 50931 Cologne, Germany, 2Department of Endocrinology, University Hospital Saint Luc, 1200 Brussels, Belgium and 3Department of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, 89019 Ulm, Germany (Correspondence should be addressed to W Arlt; Email: [email protected]) Abstract Objective: Patients with congenital adrenal hyperplasia due to P450 oxidoreductase (POR) deficiency (ORD) present with disordered sex development and glucocorticoid deficiency. This is due to disruption of electron transfer from mutant POR to microsomal cytochrome P450 (CYP) enzymes that play a key role in glucocorticoid and sex steroid synthesis. POR also transfers electrons to all major drug- metabolizing CYP enzymes, including CYP3A4 that inactivates glucocorticoid and oestrogens. However, whether ORD results in impairment of in vivo drug metabolism has never been studied. Design: We studied an adult patient with ORD due to homozygous POR A287P, the most frequent POR mutation in Caucasians, and her clinically unaffected, heterozygous mother. The patient had received standard dose oestrogen replacement from 17 until 37 years of age when it was stopped after she developed breast cancer. Methods: Both subjects underwent in vivo cocktail phenotyping comprising the oral administration of caffeine, tolbutamide, omeprazole, dextromethorphan hydrobromide and midazolam to assess the five major drug-metabolizing CYP enzymes.
    [Show full text]
  • Cytochrome P450 Enzymes in Oxygenation of Prostaglandin Endoperoxides and Arachidonic Acid
    Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 231 _____________________________ _____________________________ Cytochrome P450 Enzymes in Oxygenation of Prostaglandin Endoperoxides and Arachidonic Acid Cloning, Expression and Catalytic Properties of CYP4F8 and CYP4F21 BY JOHAN BYLUND ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2000 Dissertation for the Degree of Doctor of Philosophy (Faculty of Pharmacy) in Pharmaceutical Pharmacology presented at Uppsala University in 2000 ABSTRACT Bylund, J. 2000. Cytochrome P450 Enzymes in Oxygenation of Prostaglandin Endoperoxides and Arachidonic Acid: Cloning, Expression and Catalytic Properties of CYP4F8 and CYP4F21. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from Faculty of Pharmacy 231 50 pp. Uppsala. ISBN 91-554-4784-8. Cytochrome P450 (P450 or CYP) is an enzyme system involved in the oxygenation of a wide range of endogenous compounds as well as foreign chemicals and drugs. This thesis describes investigations of P450-catalyzed oxygenation of prostaglandins, linoleic and arachidonic acids. The formation of bisallylic hydroxy metabolites of linoleic and arachidonic acids was studied with human recombinant P450s and with human liver microsomes. Several P450 enzymes catalyzed the formation of bisallylic hydroxy metabolites. Inhibition studies and stereochemical analysis of metabolites suggest that the enzyme CYP1A2 may contribute to the biosynthesis of bisallylic hydroxy fatty acid metabolites in adult human liver microsomes. 19R-Hydroxy-PGE and 20-hydroxy-PGE are major components of human and ovine semen, respectively. They are formed in the seminal vesicles, but the mechanism of their biosynthesis is unknown. Reverse transcription-polymerase chain reaction using degenerate primers for mammalian CYP4 family genes, revealed expression of two novel P450 genes in human and ovine seminal vesicles.
    [Show full text]
  • Cholesterol Metabolites 25-Hydroxycholesterol and 25-Hydroxycholesterol 3-Sulfate Are Potent Paired Regulators: from Discovery to Clinical Usage
    H OH metabolites OH Review Cholesterol Metabolites 25-Hydroxycholesterol and 25-Hydroxycholesterol 3-Sulfate Are Potent Paired Regulators: From Discovery to Clinical Usage Yaping Wang 1, Xiaobo Li 2 and Shunlin Ren 1,* 1 Department of Internal Medicine, McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23249, USA; [email protected] 2 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; [email protected] * Correspondence: [email protected]; Tel.: +1-(804)-675-5000 (ext. 4973) Abstract: Oxysterols have long been believed to be ligands of nuclear receptors such as liver × recep- tor (LXR), and they play an important role in lipid homeostasis and in the immune system, where they are involved in both transcriptional and posttranscriptional mechanisms. However, they are increas- ingly associated with a wide variety of other, sometimes surprising, cell functions. Oxysterols have also been implicated in several diseases such as metabolic syndrome. Oxysterols can be sulfated, and the sulfated oxysterols act in different directions: they decrease lipid biosynthesis, suppress inflammatory responses, and promote cell survival. Our recent reports have shown that oxysterol and oxysterol sulfates are paired epigenetic regulators, agonists, and antagonists of DNA methyl- transferases, indicating that their function of global regulation is through epigenetic modification. In this review, we explore our latest research of 25-hydroxycholesterol and 25-hydroxycholesterol 3-sulfate in a novel regulatory mechanism and evaluate the current evidence for these roles. Citation: Wang, Y.; Li, X.; Ren, S. Keywords: oxysterol sulfates; oxysterol sulfation; epigenetic regulators; 25-hydroxysterol; Cholesterol Metabolites 25-hydroxycholesterol 3-sulfate; 25-hydroxycholesterol 3,25-disulfate 25-Hydroxycholesterol and 25-Hydroxycholesterol 3-Sulfate Are Potent Paired Regulators: From Discovery to Clinical Usage.
    [Show full text]
  • Regular Article Comparison of Inducibility of CYP1A and CYP3A Mrnas by Prototypical Inducers in Primary Cultures of Human, Cynomolgus Monkey, and Rat Hepatocytes
    Drug Metab. Pharmacokinet. 22 (3): 178–186 (2007). Regular Article Comparison of Inducibility of CYP1A and CYP3A mRNAs by Prototypical Inducers in Primary Cultures of Human, Cynomolgus Monkey, and Rat Hepatocytes Masuhiro NISHIMURA1, Akiko KOEDA2, Yasuyuki SUGANUMA2,EmakoSUZUKI2, Takefumi SHIMIZU2,MitsuoNAKAYAMA1,TetsuoSATOH2,3, Shizuo NARIMATSU4 and Shinsaku NAITO1,* 1Department of Drug Metabolism, Division of Pharmacology, Drug Safety and Metabolism, Otsuka Pharmaceutical Factory, Inc., Tokushima, Japan 2Ina Research Inc., Nagano, Japan 3Non-Proˆt Organization Human & Animal Bridging Research Organization, Chiba, Japan 4Laboratory of Health Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan Full text of this paper is available at http://www.jstage.jst.go.jp/browse/dmpk Summary: This study was conducted to investigate the eŠects of treatment with the prototypical inducers rifampicin (Rif), dexamethasone (Dex), and omeprazole (Ome) on the mRNA levels of drug- metabolizing enzymes in primary cultures of cryopreserved human, cynomolgus monkey, and rat hepatocytes. Analysis was performed by quantitative real-time RT-PCR using primers and TaqMan probes. Treatment with Ome substantially increased the mRNA levels of both CYP1A1 and CYP1A2 in human hepatocytes, but increased only the mRNA level of CYP1A1 in monkey hepatocytes, whereas it had no marked eŠect on the mRNA levels of CYP1A1 or CYP1A2 in rat hepatocytes. Treatment with Rif or Dex did not markedly aŠect the mRNA level of CYP1A in any of the hepatocyte cultures under the conditions used. All three inducers increased the mRNA level of CYP3A8 in monkey hepatocytes (in the order RifÀDexÆOme), and a similar proˆle was observed for the mRNA level of CYP3A4 in human hepatocytes, but the potency of induction was markedly attenuated.
    [Show full text]
  • TRANSLATIONALLY by AMPK a Dissertation
    CHOLESTEROL 7 ALPHA-HYDROXYLASE IS REGULATED POST- TRANSLATIONALLY BY AMPK A dissertation submitted to Kent State University in partial fulfillment of the requirements for the Degree of Doctor of Philosophy By Mauris E.C. Nnamani May 2009 Dissertation written by Mauris E. C. Nnamani B.S, Kent State University, 2006 Ph.D., Kent State University, 2009 Approved by Diane Stroup Advisor Gail Fraizer Members, Doctoral Dissertation Committee S. Vijayaraghavan Arne Gericke Jennifer Marcinkiewicz Accepted by Robert Dorman , Director, School of Biomedical Science John Stalvey , Dean, Collage of Arts and Sciences ii TABLE OF CONTENTS LIST OF FIGURES……………………………………………………………..vi ACKNOWLEDGMENTS……………………………………………………..viii CHAPTER I: INTRODUCTION……………………………………….…........1 a. Bile Acid Synthesis…………………………………………….……….2 i. Importance of Bile Acid Synthesis Pathway………………….….....2 ii. Bile Acid Transport..…………………………………...…...………...3 iii. Bile Acid Synthesis Pathway………………………………………...…4 iv. Classical Bile Acid Synthesis Pathway…..……………………..…..8 Cholesterol 7 -hydroxylase (CYP7A1)……..........………….....8 Transcriptional Regulation of Cholesterol 7 -hydroxylase by Bile Acid-activated FXR…………………………….....…10 CYP7A1 Transcriptional Repression by SHP-dependant Mechanism…………………………………………………...10 CYP7A1 Transcriptional Repression by SHP-independent Mechanism……………………………………..…………….…….11 CYP7A1 Transcriptional Repression by Activated Cellular Kinase…….…………………………...…………………….……12 v. Alternative/ Acidic Bile Acid Synthesis Pathway…………......…….12 Sterol 27-hydroxylase (CYP27A1)……………….…………….12
    [Show full text]
  • Simulation of Physicochemical and Pharmacokinetic Properties of Vitamin D3 and Its Natural Derivatives
    pharmaceuticals Article Simulation of Physicochemical and Pharmacokinetic Properties of Vitamin D3 and Its Natural Derivatives Subrata Deb * , Anthony Allen Reeves and Suki Lafortune Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL 33169, USA; [email protected] (A.A.R.); [email protected] (S.L.) * Correspondence: [email protected] or [email protected]; Tel.: +1-224-310-7870 or +1-305-760-7479 Received: 9 June 2020; Accepted: 20 July 2020; Published: 23 July 2020 Abstract: Vitamin D3 is an endogenous fat-soluble secosteroid, either biosynthesized in human skin or absorbed from diet and health supplements. Multiple hydroxylation reactions in several tissues including liver and small intestine produce different forms of vitamin D3. Low serum vitamin D levels is a global problem which may origin from differential absorption following supplementation. The objective of the present study was to estimate the physicochemical properties, metabolism, transport and pharmacokinetic behavior of vitamin D3 derivatives following oral ingestion. GastroPlus software, which is an in silico mechanistically-constructed simulation tool, was used to simulate the physicochemical and pharmacokinetic behavior for twelve vitamin D3 derivatives. The Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) Predictor and PKPlus modules were employed to derive the relevant parameters from the structural features of the compounds. The majority of the vitamin D3 derivatives are lipophilic (log P values > 5) with poor water solubility which are reflected in the poor predicted bioavailability. The fraction absorbed values for the vitamin D3 derivatives were low except for calcitroic acid, 1,23S,25-trihydroxy-24-oxo-vitamin D3, and (23S,25R)-1,25-dihydroxyvitamin D3-26,23-lactone each being greater than 90% fraction absorbed.
    [Show full text]
  • Original Article Genetic Polymorphisms in the Androgen Metabolism Pathway and Risk of Prostate Cancer in Low Incidence Malaysian Ethnic Groups
    Int J Clin Exp Med 2015;8(10):19232-19240 www.ijcem.com /ISSN:1940-5901/IJCEM0011564 Original Article Genetic polymorphisms in the androgen metabolism pathway and risk of prostate cancer in low incidence Malaysian ethnic groups Prevathe Poniah1, Zahurin Mohamed2, Yamunah Devi Apalasamy2, Shamsul Mohd Zain2, Shanggar Kuppusamy1, Azad HA Razack1 Departments of 1Surgery, 2Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malay- sia Received June 17, 2015; Accepted September 22, 2015; Epub October 15, 2015; Published October 30, 2015 Abstract: Androgens are involved in prostate cancer (PCa) cell growth. Genes involved in androgen metabolism mediate key steps in sex steroid metabolism. This study attempted to investigate whether single nucleotide poly- morphisms (SNPs) in the androgen metabolism pathway are associated with PCa risk in low incidence Asian ethnic groups. We genotyped 172 Malaysian subjects for cytochrome P450 family 17 (CYP17A1), steroid-5-alpha-reduc- tase, polypeptide 1 and 2 (SRD5A1 and SRD5A2), and insulin-like growth factor 1 (IGF-1) genes of the androgen metabolism pathway and assessed the testosterone, dihydrotestosterone and IGF-1 levels. SNPs in the CYP17A1, SRD5A1, SRD5A2, and IGF-1 genes were genotyped using real-time polymerase chain reaction. Although we did not find significant association between SNPs analysed in this study with PCa risk, we observed however, signifi- cant association between androgen levels and the IGF-1 and several SNPs. Men carrying the GG genotype for SNP rs1004467 (CYP17A1) had significantly elevated testosterone (P = 0.012) and dihydrotestosterone (DHT) levels (P = 0.024) as compared to carriers of the A allele. The rs518673 of the SRD5A1 was associated with prostate spe- cific antigen (PSA) levels.
    [Show full text]
  • Appendix: Common Steroid Identification—GC-MS Mass Spectra
    Appendix: Common Steroid Identification—GC-MS Mass Spectra Gary Woodward, Francis Lam, and Gill Rumsby As described in Chap. 3, steroid profiling in the context of steroidogenic conditions is performed by GC-MS analysis following conjugate hydrolysis and derivatisation. Below are the mass spectra used for identification of urine steroids described throughout this book, and compiled during routine practice within our laboratory. Steroids are given in approximate order of their retention times. Androstanediol (internal standard) % 100 129 256 346 107 241 331 436 215 287 372 484 516 569 637 677 0 100 150 200 250 300 350 400 450 500 550 600 650 70 Pregnadienol % 129 50 243 267 372 173 357 0 421 494 525 556 620 665 7 100 150 200 250 300 350 400 450 500 550 600 650 70 G. Woodward · G. Rumsby Department of Clinical Biochemistry, University College London Hospitals, London, UK F. Lam Level 2-Chemistry, Health Services Laboratories, London, UK © Springer International Publishing AG, part of Springer Nature 2019 177 G. Rumsby, G. M. Woodward (eds.), Disorders of Steroidogenesis, https://doi.org/10.1007/978-3-319-96364-8 178 Appendix: Common Steroid Identification—GC-MS Mass Spectra Androsterone % 100 270 360 107 147 213 253 362 0 434 461 546 610 687 100 150 200 250 300 350 400 450 500 550 600 650 700 Aetiocholanolone % 100 270 360 105 131 213 422 0 255 362 460 506 564 644 679 100 150 200 250 300 350 400 450 500 550 600 650 700 Dehydroepiandrosterone % 100 129 268 260 358 105 374 0 211 432 459 523 592 642 682 7 100 150 200 250 300 350 400 450 500
    [Show full text]
  • Mass Spectrometry-Based Steroid Profiling: Meeting Unmet Clinical Needs
    Tohoku J. Exp. Med., 2021, 253, 171-180Clinical Mass Spectrometry in Steroid Profiling 171 Invited Review for the 100th Anniversary of the TJEM Mass Spectrometry-Based Steroid Profiling: Meeting Unmet Clinical Needs Man Ho Choi1 1Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea Despite ongoing concerns regarding its clinical application, mass spectrometry (MS)-based steroid assay represents a promising tool in endocrine research. Recent studies indicate that monitoring the blood levels of individual sterols provides improved diagnostic insight into hyperlipidemia compared with immunoassays routinely used in clinical practice. Hypercortisolism and hyperaldosteronism can also be easily evaluated along with successful subtyping of adrenal diseases using MS-based methods, while metabolic signatures of sex steroids provide experimental evidence of abnormal puberty and male infertility. Many MS-based biological and clinical studies are based on liquid chromatography-mass spectrometry (LC-MS) coupled to electrospray ionization and tandem MS scan modes. However, gas chromatography-mass spectrometry (GC-MS) provides better chromatographic separation. Improved chromatographic resolution enables large- scale steroid profiling to allow a bird-eye view and increase the chances of identifying potent biomarkers in endocrine research. In addition to the technical advantages of MS-based assays over immunoassays, minimizing the sample amounts with acceptable analytical sensitivity and standardization of surrogate materials provides cutting-edge tools for precision and personalized medicine. Keywords: adrenal gland; cholesterol; clinical application; mass spectrometry; steroids Tohoku J. Exp. Med., 2021 March, 253(3), 171-180. known relevance of receptor expression in disease behavior, Introduction such as glucocorticoids in Cushing’s syndrome and estro- Immunoaffinity techniques are easy to use in clinical gens in both breast cancer and osteoporosis (Jordan et al.
    [Show full text]
  • Eagling Differential Selectivity of CYP Inhibitors Against Probe Substrates
    Br J Clin Pharmacol 1998; 45: 107–114 Differential selectivity of cytochrome P450 inhibitors against probe substrates in human and rat liver microsomes Victoria A. Eagling, John F. Tjia & David J. Back Department of Pharmacology & Therapeutics, University of Liverpool, P.O. Box 147, Liverpool L69 3GE, UK Aims Chemical inhibitors of cytochrome P450 (CYP) are a useful tool in defining the role of individual CYPs involved in drug metabolism. The aim of the present study was to evaluate the selectivity and rank the order of potency of a range of isoform-selective CYP inhibitors and to compare directly the eVects of these inhibitors in human and rat hepatic microsomes. Methods Four chemical inhibitors of human cytochrome P450 isoforms, furafylline (CYP1A2), sulphaphenazole (CYP2C9), diethyldithiocarbamate (CYP2E1), and ketoconazole (CYP3A4) were screened for their inhibitory specificity towards CYP- mediated reactions in both human and rat liver microsomal preparations. Phenacetin O-deethylation, tolbutamide 4-hydroxylation, chlorzoxazone 6-hydroxylation and testosterone 6b-hydroxylation were monitored for enzyme activity. Results Furafylline was a potent, selective inhibitor of phenacetin O-deethylation = (CYP1A2-mediated) in human liver microsomes (IC50 0.48 mm), but inhibited both phenacetin O-deethylation and tolbutamide 4-hydroxylation (CYP2C9- mediated) at equimolar concentrations in rat liver microsomes (IC50=20.8 and 24.0 mm respectively). Sulphaphenazole demonstrated selective inhibition of tolbutamide hydroxylation in human liver microsomes but failed to inhibit this reaction in rat liver microsomes. DDC demonstrated a low level of selectivity as an inhibitory probe for chlorzoxazone 6-hydroxylation (CYP2E1-mediated). DDC also inhibited testosterone 6b-hydroxylation (CYP3A-mediated) in man and rat, and tolbutamide 4-hydroxylase activity in rat.
    [Show full text]
  • Recent Advances in P450 Research
    The Pharmacogenomics Journal (2001) 1, 178–186 2001 Nature Publishing Group All rights reserved 1470-269X/01 $15.00 www.nature.com/tpj REVIEW Recent advances in P450 research JL Raucy1,2 ABSTRACT SW Allen1,2 P450 enzymes comprise a superfamily of heme-containing proteins that cata- lyze oxidative metabolism of structurally diverse chemicals. Over the past few 1La Jolla Institute for Molecular Medicine, San years, there has been significant progress in P450 research on many fronts Diego, CA 92121, USA; 2Puracyp Inc, San and the information gained is currently being applied to both drug develop- Diego, CA 92121, USA ment and clinical practice. Recently, a major accomplishment occurred when the structure of a mammalian P450 was determined by crystallography. Correspondence: Results from these studies will have a major impact on understanding struc- JL Raucy,La Jolla Institute for Molecular Medicine,4570 Executive Dr,Suite 208, ture-activity relationships of P450 enzymes and promote prediction of drug San Diego,CA 92121,USA interactions. In addition, new technologies have facilitated the identification Tel: +1 858 587 8788 ext 116 of several new P450 alleles. This information will profoundly affect our under- Fax: +1 858 587 6742 E-mail: jraucyȰljimm.org standing of the causes attributed to interindividual variations in drug responses and link these differences to efficacy or toxicity of many thera- peutic agents. Finally, the recent accomplishments towards constructing P450 null animals have afforded determination of the role of these enzymes in toxicity. Moreover, advances have been made towards the construction of humanized transgenic animals and plants. Overall, the outcome of recent developments in the P450 arena will be safer and more efficient drug ther- apies.
    [Show full text]
  • Pulmonary Prostacyclin Synthase Overexpression Chemoprevents Tobacco Smoke Lung Carcinogenesis in Mice
    [CANCER RESEARCH 64, 5897–5904, August 15, 2004] Pulmonary Prostacyclin Synthase Overexpression Chemoprevents Tobacco Smoke Lung Carcinogenesis in Mice Robert L. Keith,1,2 York E. Miller,1,2 Tyler M. Hudish,1 Carlos E. Girod,5 Sylk Sotto-Santiago,2 Wilbur A. Franklin,3 Raphael A. Nemenoff,4 Thomas H. March,6 S. Patrick Nana-Sinkam,2 and Mark W. Geraci2 1Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, Denver VA Medical Center, Denver, Colorado; 2Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, 3Department of Pathology, and 4Departments of Medicine and Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado; 5Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; and 6Inhalation Toxicology Laboratory, Lovelace Respiratory Research Institute, Albuquerque, New Mexico ABSTRACT lung tumors. These chemicals induce murine adenocarcinomas that contain many of the same histological and genetic alterations found in Increased pulmonary production of prostaglandin I (prostacyclin) by 2 human adenocarcinomas (3). To directly address concerns that single lung-specific overexpression of prostacyclin synthase decreases lung tu- or multiple carcinogen injection may not best the model lung tumor mor incidence and multiplicity in chemically induced murine lung cancer models. We hypothesized that pulmonary prostacyclin synthase overex- development in humans, animal models of tobacco smoke exposure pression would prevent lung carcinogenesis in tobacco-smoke exposed have been developed and tested. Tobacco smoke is a mouse lung mice. Murine exposure to tobacco smoke is an established model of carcinogen and can reproducibly induce pulmonary adenocarcinomas inducing pulmonary adenocarcinomas and allows for the testing of po- (4).
    [Show full text]